Huntingtin and the control of long distance transport of synaptic / extrasynaptic signals in health and disease

亨廷顿蛋白（HTT）是一种蛋白质，一旦发生突变，就会导致亨廷顿病（HD）。亨廷顿病是一种毁灭性的神经系统疾病，它可以作为蛋白质复合物的支架，在轴突和树突的囊泡和蛋白质运输中发挥新的作用。HTT与分子马达动力蛋白和动力蛋白相互作用，调节转运的有效性和方向性，使HTT处于调节轴突和树突长距离信号转运的功能节点的中心。在疾病的早期阶段，不存在结构性损伤，但突触功能受损，表现为从突触向突触外n -甲基- d -天冬氨酸受体（NMDAR）信号传导的转变。Jacob是一种突触-核蛋白信使，编码和转导NMDAR信号的突触或突触外起源到细胞核，并在导致细胞死亡或促进细胞存活和突触可塑性的基因表达调控中发挥作用。核运输雅各布需要一个积极的进口和动力蛋白介导逆行运输沿微管。几项研究提供了令人信服的证据，证明亨廷顿蛋白与参与基因转录、细胞信号传导和细胞内运输的蛋白质相互作用。最近的报道表明，亨廷顿蛋白可能提供了一个平台，将转录调节因子与分子马达连接起来，从突触运输到细胞核。通过这个提议，我们将解决这个问题。我们还将研究微管转运的扰动是否会导致HD的长距离信号传导受损。更具体地说，我们提出HTT和Jacob可能在整合突触到细胞核的远程信号中发挥重要作用，从而改变健康和HD患者的基因表达。我们假设Jacob（一种可以将nmdar衍生的信号体连接到核靶点的蛋白质）和突变的HTT之间的功能相互作用可能导致HD的神经退行性变。我们将测试HTT和Jacob是否直接相互作用，我们的目标是确定在正常和HD条件下转运到细胞核的信号的分子身份，特别强调转录调控因子的非囊泡转运。最重要的是，我们想要评估突触外NMDAR是否会触发HD患者的Jacob核输入，以及这与细胞死亡和神经退行性变之间的关系。综上所述，本研究将进一步揭示被忽视的HTT的生理功能，同时我们将了解所研究的机制如何影响疾病的病理生理。

Huntingtin (HTT) the protein that when mutated causes Huntingtons disease (HD), a devastating neurological disorder acts as a scaffold for protein complexes with an emerging role in the transport of vesicles and proteins in axons and dendrites. HTT interacts with the molecular motors dynein and kinesin to regulate the efficacy and the directionality of transport placing HTT at the center of functional nodes that regulate the transport of signals over long distances in axons and dendrites. At an early stage of the disease no structural damage exists but rather an impairment of synaptic function that manifests in a shift from synaptic to extrasynaptic N-Methyl-D-Aspartate-receptor (NMDAR) signalling. Jacob is a synapto-nuclear protein messenger that encodes and transduces the synaptic or extra-synaptic origin of NMDAR signals to the nucleus and that plays a role in regulation of gene expression either leading to cell death or promoting cell survival and synaptic plasticity. Nuclear trafficking of Jacob requires an active importin- and dynein- mediated retrograde transport along microtubuli. Several studies have provided compelling evidence that huntingtin interacts with proteins which are involved in gene transcription, cell signaling and intracellular transport. Very recent reports suggest that huntingtin might provide a platform that links transcriptional regulators to molecular motors for transport from synapse to nucleus. With this proposal we will address this idea. We will also investigate whether perturbation of microtubule-based transport contributes to impairments in long-distance signalling in HD. More specifically we propose that HTT and Jacob could play a major role in integrating long-range signals from the synapse to the nucleus and consequently will modify gene expression in health and in HD. We assume that a functional interplay between Jacob, a protein that can dock an NMDAR-derived signalosome to nuclear target sites and mutant HTT might contribute to neurodegeneration in HD. We will test whether HTT and Jacob interact directly and we aim to determine the molecular identity of the signals transported to the nucleus in normal and HD conditions with special emphasis on non-vesicular transport of transcriptional regulators. Most important we want to assess whether extrasynaptic NMDAR trigger nuclear import of Jacob in HD and how this relates to cell death and neurodegeneration. Taken together the proposed work program will shed new light on the physiological function of HTT, which has been neglected and at the same time we will learn how the investigated mechanisms impacts on the pathophysiology of the disease.